Impact of APOE on endothelial cell proteomes in Alzheimer's disease

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ABSTRACT (PROJECT SUMMARY) Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that results in deposition of amyloid-b (Ab) peptide in brain parenchyma and cerebral blood vessels as cerebral amyloid angiopathy (CAA). Genome- wide association studies (GWAS) have identified numerous genes altering AD risk with the e4 allele of apolipoprotein E (APOE4) showing the strongest association with AD and CAA. APOE4 modulates amyloid accumulation in cerebrovasculature and impacts the efficiency of Ab clearance from the brain. In addition, APOE4 carriers exhibit accelerated breakdown of the blood-brain barrier (BBB) and higher risk for cerebrovascular dysfunction during normal aging. However, the underlying mechanisms of this genetic susceptibility on cerebrovascular function and pathology are still poorly understood. Recent work from our group revealed APOE-driven protein perturbations associated with endothelial cells in the postmortem brain tissue from AD individuals. Yet, these observations come from bulk brain tissue limiting the ability to dissect cell-type specific proteomic changes. Thus, the major goal of this proposal is to molecularly define the endothelial cells in the context of APOE-associated amyloidosis. I hypothesize that APOE4 genotype directly impacts endothelial proteome leading to the BBB dysfunction and breakdown. In Aim 1, I will perform an unbiased proteomic analysis of isolated cerebral blood vessels from cortical tissues of AD, AD with severe CAA, asymptomatic AD (AsymAD, individuals exhibiting amyloid and tau accumulation in the brain with no cognitive decline), and non-demented control individuals. I will further apply integrative analysis to the brain vascular proteomes and previously generated proteomic data of cerebrospinal fluid (CSF) to identify AD CSF biomarkers that mirror pathological changes of the cerebrovasculature. In Aim 2, I will explore in vivo effect of APOE and amyloid on endothelial cell proteome by taking advantage of highly innovative, recently developed by our group approach that allows for Cell-type specific In-vivo Biotinylation of Proteins followed by mass-spectrometry (CIBOP-MS). Dissecting proteomes of endothelial cells in a disease setting will be a conceptual advancement and a crucial step towards understanding the mechanisms underlying AD-related BBB breakdown, diminished blood flow, and pathological accumulation of amyloid in the cerebrovasculature.